The overall objective of the present Program Project is to continue our comprehensive examination of the cellular alterations responsible for the development and perpetuation of the cell injury induced by ischemic and toxic insults to the kidney. A structured approach to delineating the cellular and biochemical steps in the pathogenesis of renal cell injury has been designed in each section of the grant. In Section I, the isolated proximal tubule preparation will be used to investigate the direct effects of anoxia and hypoxia on cellular processes without any obscuring hemodynamic effects. Section II will examine the vascular mechanisms involved in the evolution of cyclosporine nephropathy using the isolated small artery and arteriole technique as well as renal adrenergic and hemodynamic measurements in the intact rat. Section III will examine the intracellular targets within vascular smooth muscle and proximal tubule epithelial cells in culture which are susceptible to attack by activated neutrophils. The Administrative Core Section will provide overall administration of these three projects as well as secretarial support for the Program Project. The Research Core Section will be utilized by each of three projects. The instrumentation will be available in one central location and will permit uniform analysis of mitochondrial/tissue respiration, intracellular Ca2+ and tissue/urine/plasma electrolytes. The ultimate goal of this proposal is the utilization of the information obtained from this multidisciplinary approach to serve as a basis for the development of appropriate preventive and therapeutic strategies.